Cyproheptadine treatment in Cushing’s disease (original) (raw)
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Pituitary-directed medical treatment of Cushing’s disease
Expert Review of Endocrinology & Metabolism, 2009
The treatment of Cushing's disease is very complex and represents a challenge for clinicians. Transphenoidal surgical excision of adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma remains the treatment of choice but, unfortunately, the rate of cure at long-term follow-up is suboptimal and recurrences are high, even in the hands of skilled neurosurgeons. Other treatments options, such as bilateral adrenalectomy and pituitary radiotherapy, are currently in use but no treatment has proven to be fully satisfactory during the lengthy progress of this chronic and devastating disease. Nelson's syndrome and hypopituitarism are of particular concern as affected patients need lifelong hormone-replacement therapy and have notably increased mortality. Although medical treatment represents a second-line treatment option in patients with Cushing's Disease, so far pharmacological therapy has been considered a transient and palliative treatment. Many drugs have been employed: they may act at the hypothalamicpituitary level, decreasing ACTH secretion; at the adrenal level, inhibiting cortisol synthesis (steroidogenesis inhibitors), or at the peripheral level by competing with cortisol (glucocorticoid receptor antagonist). Recently there has been renewed interest in the medical therapy of Cushing's disease and pituitary-directed drugs include old compounds commercially available for other diseases, such as cabergoline, and new promising compounds, such as pasireotide (SOM230) or retinoic acid. This review focuses on the tumor-directed pharmacological approaches for the management of Cushing's disease based on the recent identification of possibile targets at a pituitary level.
Management Strategies for Aggressive Cushing's Syndrome: From Macroadenomas to Ectopics
2012
Cushing's syndrome (CS) is a rare but severe clinical condition represented by an excessive endogenous cortisol secretion and hence excess circulating free cortisol, characterized by loss of the normal feedback regulation and circadian rhythm of the hypothalamicpituitary axis due to inappropriate secretion of ACTH from a pituitary tumor (Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic goal is the removal of the tumor. Whenever surgery is not curative, management of patients with CS requires a major effort to control hypercortisolemia and associated symptoms. A multidisciplinary approach that includes endocrinologists, neurosurgeons, oncologists, and radiotherapists should be adopted. This paper will focus on traditional and novel medical therapy for aggressive ACTH-dependent CS. Several drugs are able to reduce cortisol levels. Their mechanism of action involves blocking adrenal steroidogenesis (ketoconazole, metyrapone, aminoglutethimide, mitotane, etomidate) or inhibiting the peripheral action of cortisol through blocking its receptors (mifepristone "RU-486"). Other drugs include centrally acting agents (dopamine agonists, somatostatin receptor agonists, retinoic acid, peroxisome proliferator-activated receptor γ "PPAR-γ" ligands) and novel chemotherapeutic agents (temozolomide and tyrosine kinase inhibitors) which have a significant activity against aggressive pituitary or ectopic tumors.
Medical treatment of Cushing's disease: Overview and recent findings
International Journal of General Medicine, 2009
Cushing's disease, due to pituitary adrenocorticotropic hormone (ACTH) hypersecretion, is the most common etiology of spontaneous excess cortisol production. The majority of pituitary tumors causing Cushing's disease measure 1 cm and the excess morbidity associated with these tumors is mostly due to the effects of elevated, nonsuppressible, ACTH levels leading to adrenal steroid hypersecretion. Elevated circulating cortisol levels lead to abnormal fat deposition, hypertension, diabetes, coronary artery disease, osteoporosis, muscle weakness and psychological disturbances. At experienced centers, initial surgical remission rate via transnasal, transphenoidal resection approaches 80% for tumors less than 1 cm, but may be as low as 30% for larger lesions and long-term recurrence in all groups approaches 25%. Residual disease may be managed with more radical surgery, pituitary-directed radiation, bilateral adrenalectomy, or medical therapy. This paper addresses current and novel therapies in various stages of development for Cushing's disease.
Archives of endocrinology and metabolism, 2018
The treatment objectives for a patient with Cushing's disease (CD) are remission of hypercortisolism, adequate management of co-morbidities, restoration of the hypothalamic-pituitary-adrenal axis, preservation of fertility and pituitary function, and improvement of visual defects in cases of macroadenomas with suprasellar extension. Transsphenoidal pituitary surgery is the main treatment option for the majority of cases, even in macroadenomas with low probability of remission. In cases of surgical failure, another subsequent pituitary surgery might be indicated in cases with persistent tumor imaging at post surgical magnetic resonance imaging (MRI) and/or pathology analysis of adrenocorticotropic hormone-positive (ACTH+) positive pituitary adenoma in the first procedure. Medical treatment, radiotherapy and adrenalectomy are the other options when transsphenoidal pituitary surgery fails. There are several options of medical treatment, although cabergoline and ketoconazole are the...
New developments in the medical treatment of Cushing's syndrome
Endocrine-Related Cancer, 2012
Cushing's syndrome (CS) is a severe endocrine disorder characterized by chronic cortisol excess due to an ACTH-secreting pituitary adenoma, ectopic ACTH production, or a cortisol-producing adrenal neoplasia. Regardless of the underlying cause, untreated CS is associated with considerable morbidity and mortality. Surgery is the primary therapy for all causes of CS, but surgical failure and ineligibility of the patient to undergo surgery necessitate alternative treatment modalities. The role of medical therapy in CS has been limited because of lack of efficacy or intolerability. In recent years, however, new targets for medical therapy have been identified, both at the level of the pituitary gland (e.g. somatostatin, dopamine, and epidermal growth factor receptors) and the adrenal gland (ectopically expressed receptors in ACTH-independent macronodular adrenal hyperplasia). In this review, results of preclinical and clinical studies with drugs that exert their action through these ...
Medical management of Cushing disease
Neurosurgical Focus, 2007
✓Although transsphenoidal excision of the adrenocorticotropic hormone (ACTH)–producing neoplasm is often the treatment of choice in patients with Cushing disease, medical management is itself a useful preoperative temporizing measure, an option for long-term management in nonsurgical candidates, and an option for patients in whom surgery and/or radiotherapy have failed. Three pathophysiologically based approaches exist in the research literature—neuro-modulation to limit ACTH levels, adrenal enzyme inhibition, and glucocorticoid receptor antagonism. Unfortunately, the neuromodulatory approach involving agents such as bromocriptine, cyproheptadine, octreotide, and valproate has yielded only suboptimal results. Glucocorticoid receptor antagonism remains in its infancy but may overall be limited by side effects and a resultant increase in ACTH and cortisol levels. Adrenal enzyme inhibitors, however, offer substantial future promise in the management of Cushing disease but are limited b...
Treatment Options in Cushing's Disease
Clinical Medicine Insights. Oncology, 2012
Endogenous Cushing's syndrome is a grave disease that requires a multidisciplinary and individualized treatment approach for each patient. Approximately 80% of all patients harbour a corticotroph pituitary adenoma (Cushing's disease) with excessive secretion of adrenocorticotropin-hormone (ACTH) and, consecutively, cortisol. The goals of treatment include normalization of hormone excess, long-term disease control and the reversal of comorbidities caused by the underlying pathology. The treatment of choice is neurosurgical tumour removal of the pituitary adenoma. Second-line treatments include medical therapy, bilateral adrenalectomy and radiation therapy. Drug treatment modalities target at the hypothalamic/pituitary level, the adrenal gland and at the glucocorticoid receptor level and are commonly used in patients in whom surgery has failed. Bilateral adrenalectomy is the second-line treatment for persistent hypercortisolism that offers immediate control of hypercortisoli...
Cushing\'s Disease Arising from a Clinically Nonfunctioning Pituitary Adenoma
Endocrine Pathology, 2006
A 49-yr-old woman with a large pituitary tumor leading to visual loss and galactorrheaamenorrhea was submitted to transcranial pituitary surgery, when a clinically nonfunctioning pituitary adenoma was partially removed. Histopathology and immunohistochemistry confirmed the diagnosis of "non-secreting atypical adenoma." At that time, serum and urinary free cortisol were normal, with low T4 levels and hyperprolactinemia. The patient was discharged on thyroxine and bromocriptine and treated with conventional radiotherapy. Two years later, she presented high free urinary cortisol levels and a positive ACTH response to desmopressin testing on dexametasone 2 mg overnight. A pituitary biopsy confirmed aggressive growth as well as positive immunoreactivity for ACTH, p53, Ki-67, and c-erb-B2. The patient was then treated with radiosurgery on ketoconazole therapy. The overall clinical, laboratory, and pathological data suggest a transition from a clinically nonfunctioning to a hypersecreting ACTH-producing tumor. Putative mechanisms of tumor transformation and the possibility of a silent corticotropinoma evolving into clinical Cushing´s syndrome are discussed.
The Treatment of Cushing's Disease
Endocrine Reviews, 2015
Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy h...